ABSTRACT The purpose of this study is to determine whether oral memantine daily for 6 months, when compared to placebo, is associated with reduction in decline of cognitive function at 12 months in children ages 4-18 receiving cranial radiotherapy (RT) for primary central nervous system tumors and to correlate protective effects of memantine with imaging biomarkers. Radiotherapy is a proven curative therapeutic tool in the treatment of primary brain tumors. However, cranial RT results in significant cognitive morbidity. The mechanisms of radiation-induced injury result in a picture that is a combination of the small vessel disease seen with vascular dementia as well as neurodegenerative diseases like Alzheimer?s dementia. Ischemia and injury can induce excessive NMDA stimulation and lead to excitotoxicity, and pre- clinical data suggests that selective blocking of the NMDA receptor can restore long-term potentiation and restore learning in both models of ischemia as well as models of radiation injury. Memantine is a non- competitive, low-affinity, open- channel NMDA blocker, which has been shown to be neuroprotective in pre- clinical models. In two placebo- controlled phase III trials, memantine proved to be effective treatment for Alzheimer?s and vascular dementia, especially for patients with small-vessel disease. Memantine has also proven effective in reducing cognitive dysfunction in adults receiving whole-brain radiotherapy for brain metastases. Memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function and processing speed. Importantly, cognitive function in patients receiving memantine remained stable even after memantine was discontinued; suggesting memantine had a protective effect rather than simply a therapeutic effect. In this study, we propose evaluating the efficacy of memantine in preventing cognitive dysfunction in pediatric patients receiving cranial radiation through the clinical trial mechanism of the Children?s Oncology Group. This study is novel in that children will undergo early cognitive evaluations (baseline prior to radiation, 3, 6, and 12 months post-radiation) with a brief computerized testing battery that we will correlate with formal cognitive testing as well with long-term cognitive function (30 and 60 months) assessed with both methods. If successful, this study will provide validated early cognitive assessment time points that correlate with late cognitive toxicity and result in an framework for accelerated study design that will allow for early assessment of efficacy for future neuro-protectant trials. Dose- and volume-dependent reduction in brain volume is seen after radiotherapy exposure and is associated with cognitive decline. We hypothesize that neuroprotection with memantine will also preserve relevant brain volume and this will correlate with domain- specific improvements in cognitive function. We will use quantitative volumetric MRI analysis to correlate protective effects of memantine with brain substructure (white matter, hippocampus, frontal lobes etc) volume changes over time and correlate with cognitive assessments. Radiographic analysis will provide proof-of- principle for the mechanism of action of memantine as well as a biomarker that can be utilized in future trials of radio-protectants, which is especially important for young patients or patients not neurologically capable of completing cognitive assessments but who may benefit the most from neuroprotective interventions.